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Background: Individual genetic variability may influence the course of multiple sclerosis (MS). The interleukin (IL)-8C>T rs2227306 single nucleotide polymorphism (SNP) regulates IL-8 activity in other clinical conditions; however, its role in MS has never been investigated. Objectives: To explore the association between IL-8 SNP rs2227306, cerebrospinal fluid (CSF) IL-8 concentrations, clinical, and radiological characteristics in a group of newly diagnosed MS patients. Methods: In 141 relapsing-remitting (RR)-MS patients, rs2227306 polymorphism, CSF levels of IL-8, clinical, and demographical characteristics were determined. In 50 patients, structural magnetic resonance imaging (MRI) measures were also assessed. Results: An association between CSF IL-8 and Expanded Disability Status Scale (EDSS) at diagnosis was found in our set of patients ( r = 0.207, p = 0.014). CSF IL-8 concentrations were significantly higher in patients carrying the T variant of rs2227306 ( p = 0.004). In the same group, a positive correlation emerged between IL-8 and EDSS ( r = 0.273, p = 0.019). Finally, a negative correlation between CSF levels of IL-8 and cortical thickness emerged in rs2227306T carriers ( r = −0.498, p = 0.005). Conclusion: We describe for the first time a role of SNP rs2227306 of IL-8 gene in regulating the expression and the activity of this inflammatory cytokine in MS.

(1) Background: The clinical course of multiple sclerosis (MS) is critically influenced by the expression of different pro-inflammatory and anti-inflammatory cytokines. Interleukin 6 (IL-6) represents a major inflammatory molecule previously associated with exacerbated disease activity in relapsing remitting MS (RR-MS); however, the role of single-nucleotide polymorphisms (SNPs) in the IL-6 gene has not been fully elucidated in MS. (2) Methods: We explored in a cohort of 171 RR-MS patients, at the time of diagnosis, the associations between four IL-6 SNPs (rs1818879, rs1554606, rs1800797, and rs1474347), CSF inflammation, and clinical presentation. (3) Results: Using principal component analysis and logistic regression analysis we identified an association between rs1818879, radiological activity, and a set of cytokines, including the IL-1β, IL-9, IL-10, and IL-13. No significant associations were found between other SNPs and clinical or inflammatory parameters. (4) Conclusions: The association between the rs1818879 polymorphism and subclinical neuroinflammatory activity suggests that interindividual differences in the IL-6 gene might influence the immune activation profile in MS.

In recent years, experimental studies have clarified that immune system influences the functioning of the central nervous system (CNS) in both physiologic and pathologic conditions. The neuro-immune crosstalk plays a crucial role in neuronal development and may be critically involved in mediating CNS response to neuronal damage. Multiple sclerosis (MS) represents a good model to investigate how the immune system regulates neuronal activity. Accordingly, a growing body of evidence has demonstrated that increased levels of pro-inflammatory mediators may significantly impact synaptic mechanisms, influencing overall neuronal excitability and synaptic plasticity expression. In this chapter, we provide an overview of preclinical data and clinical studies exploring synaptic functioning noninvasively with transcranial magnetic stimulation (TMS) in patients with MS. Moreover, we examine how inflammation-driven synaptic dysfunction could affect synaptic plasticity expression, negatively influencing the MS course. Contrasting CSF inflammation together with pharmacologic enhancement of synaptic plasticity and application of noninvasive brain stimulation, alone or in combination with rehabilitative treatments, could improve the clinical compensation and prevent the accumulating deterioration in MS.

Background: Synaptic plasticity helps in reducing the clinical expression of brain damage and represents a useful mechanism to compensate the negative impact of new brain lesions in multiple sclerosis (MS). Inflammation, altering synaptic plasticity, could negatively influence the disease course in relapsing-remitting MS (RR-MS). Objective: In the present study, we explored whether interleukin (IL)-6, a major proinflammatory cytokine involved in MS pathogenesis, alters synaptic plasticity and affects the ability to compensate for ongoing brain damage. Methods: The effect of IL-6 incubation on long-term potentiation (LTP) induction was explored in vitro, in mice hippocampal slices. We also explored the correlation between the cerebrospinal fluid (CSF) levels of this cytokine and the LTP-like effect induced by the paired associative stimulation (PAS) in a group of RR-MS patients. Finally, we examined the correlation between the CSF levels of IL-6 at the time of diagnosis and the prospective disease activity in a cohort of 150 RR-MS patients. Results: In vitro LTP induction was abolished by IL-6. Consistently, in patients with MS, a negative correlation emerged between IL-6 CSF concentrations and the effect of PAS. In MS patients, longer disease duration before diagnosis was associated with higher IL-6 CSF concentrations. In addition, elevated CSF levels of IL-6 were associated with greater clinical expression of new inflammatory brain lesions, unlike in patients with low or absent IL-6 concentrations, who had a better disease course. Conclusions: IL-6 interfering with synaptic plasticity mechanisms may impair the ability to compensate the clinical manifestation of new brain lesions in RR-MS patients.

The clinical course of multiple sclerosis (MS) is critically influenced by the interplay between inflammatory and neurodegenerative processes. The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265), one of the most studied single-nucleotide polymorphisms (SNPs), influences brain functioning and neurodegenerative processes in healthy individuals and in several neuropsychiatric diseases. However, the role of this polymorphism in MS is still controversial. In 218 relapsing–remitting (RR)-MS patients, we explored, at the time of diagnosis, the associations between the Val66Met polymorphism, clinical characteristics, and the cerebrospinal fluid (CSF) levels of a large set of pro-inflammatory and anti-inflammatory molecules. In addition, associations between Val66Met and structural MRI measures were assessed. We identified an association between the presence of Met and a combination of cytokines, identified by principal component analysis (PCA), including the pro-inflammatory molecules MCP-1, IL-8, TNF, Eotaxin, and MIP-1b. No significant associations emerged with clinical characteristics. Analysis of MRI measures evidenced reduced cortical thickness at the time of diagnosis in patients with Val66Met. We report for the first time an association between the Val66Met polymorphism and central inflammation in MS patients at the time of diagnosis. The role of this polymorphism in both inflammatory and neurodegenerative processes may explain its complex influence on the MS course.

Multiple sclerosis (MS) is an inflammatory immune-mediate disorder of the central nervous system (CNS), primarily affecting the myelin sheath and followed by neurodegeneration. Synaptic alterations are emerging as critical determinants of early neurodegeneration in MS. Inflammation-induced alterations of synaptic transmission and plasticity have been investigated in vitro and also in human MS using transcranial magnetic stimulation (TMS) techniques. Specific inflammatory cytokines alter glutamatergic and GABAergic transmission, resulting in synaptic hyperexcitability. In both experimental autoimmune encephalomyelitis (EAE) and MS, excitotoxic damage and neurodegeneration are found even in the early phases of disease, conversely inflammation persists in the progressive phases. Inflammatory cytokines also affect synaptic plasticity, as both long-term potentiation (LTP) and long-term depression (LTD) are altered in EAE and in MS patients. In particular, inflammation profoundly subverts plasticity and influence both clinical recovery after a relapse and disease course. Regulation of neuronal activity by cytokines plays important roles in the neuro-immune crosstalk involved in inflammation-associated excitotoxic neuronal damage, and in the chance of developing compensatory plasticity. Innate and adaptive immunity interact with the CNS in MS, in line with the concept that cytokines and chemokines, in concert with neurotransmitters and neuropeptides, represent a major communication system in the CNS.

The endocannabinoid system plays a regulatory role in a number of physiological processes and has been found altered in different pathological conditions, including movement disorders. The interactions between cannabinoids and dopamine in the basal ganglia are remarkably complex and involve both the modulation of other neurotransmitters (γ-aminobutyric acid, glutamate, opioids, peptides) and the activation of different receptors subtypes (cannabinoid receptor type 1 and 2). In the last years, experimental studies contributed to enrich this scenario reporting interactions between cannabinoids and other receptor systems (transient receptor potential vanilloid type 1 cation channel, adenosine receptors, 5-hydroxytryptamine receptors). The improved knowledge, adding new interpretation on the biochemical interaction between cannabinoids and other signaling pathways, may contribute to develop new pharmacological strategies. A number of preclinical studies in different experimental Parkinson's disease (PD) models demonstrated that modulating the cannabinoid system may be useful to treat some motor symptoms. Despite new cannabinoid-based medicines have been proposed for motor and nonmotor symptoms of PD, so far, results from clinical studies are controversial and inconclusive. Further clinical studies involving larger samples of patients, appropriate molecular targets, and specific clinical outcome measures are needed to clarify the effectiveness of cannabinoid-based therapies.

Background and Aims: Interferon beta (IFNb) is a safe first-line drug commonly used for relapsing-remitting (RR)-MS. Nevertheless, a considerable proportion of patients do not respond to IFNb treatment. Therefore, until now, a number of studies have investigated various markers that could predict the patients who would respond to IFNb therapy. The objective of this study was to identify reliable biomarkers to predict the efficacy of IFNb treatment in MS. Methods: In a group of 116 patients with clinically isolated syndrome (CIS) and RR-MS, we explored the association between CSF detectability of a large set of proinflammatory and anti-inflammatory molecules at the time of diagnosis and response to IFNb after the first year of treatment. The absence of clinical relapses, radiological activity and disability progression (NEDA-3) was assessed at the end of 1-year follow up. The results were compared with those obtained in additional groups of CIS and RR-MS patients treated with other first-line drugs (dimethyl fumarate and glatiramer acetate). Results: CSF undetectability of macrophage inflammatory protein (MIP)-1α was the main predictor of reaching NEDA-3 status after 1 year of IFNb treatment. Moreover, detectable platelet-derived growth factor (PDGF) was associated with higher probability of reaching NEDA-3. Conversely, no associations with the CSF molecules were found in the two other groups of patients treated either with dimethyl fumarate or with glatiramer acetate. Conclusion: MIP-1α and PDGF could potentially represent suitable CSF biomarkers able to predict response to IFNb in MS.

Objectives Skill acquisition after motor training involves synaptic long-term potentiation (LTP) in primary motor cortex (M1). In multiple sclerosis (MS), LTP failure ensuing from neuroinflammation could contribute to worsen clinical recovery. We therefore addressed whether practice-dependent plasticity is altered in MS. Methods Eighteen relapsing-remitting (RR)-MS patients and eighteen healthy controls performed 600 fast abductions of index finger in 30 blocks of 20 movements. Before and after practice, transcranial magnetic stimulation (TMS) was delivered over the hot spot of the trained first dorsal interosseous muscle. Movements kinematics, measures of cortical excitability, and the input/output curves of motor evoked potentials (MEPs) were assessed. Results Kinematic variables of movement improved with practice in patients and controls to a similar extent, although patients showed lower MEPs amplitude increase after practice. Practice did not change the difference in resting motor threshold values observed between patients and controls, nor did modulate short-interval intracortical inhibition. Clinical/radiological characteristics were not associated to practice-dependent effects. Conclusions Practice-induced reorganization of M1 is altered in non-disabled RR-MS patients, as shown by impaired MEPs modulation after motor learning. Significance These findings suggest that in RR-MS physiological mechanisms of practice-dependent plasticity are altered.

Background Many studies have shown that migraine patients have an interictal habituation deficit of visual evoked potentials (VEPs). Some discordant results were attributed to non-blinded analyses and a lack of repeatability. Aims In this study, we compared blinded and non-blinded analyses of the same recordings and assessed test–retest repeatability. Methods VEP recordings of 25 healthy volunteers (HVs) and 78 episodic migraine patients (EMs; 52 interictal, 26 ictal) were analysed by two investigators, one of whom was blinded to diagnosis and headache phase. Twelve HVs and nine EMs had two recordings for test repeatability. Results In both blinded and non-blinded analyses, VEP habituation was normal in HVs and EMs during an attack, but deficient in EMs interictally. Intra-individual habituation percentages were highly correlated in two recordings separated by ≥7 days. Conclusions The studies showing a VEP habituation deficit in migraineurs between attacks are unlikely to be biased by non-blinding analysis or poor repeatability.

In multiple sclerosis (MS), inflammation alters synaptic transmission and plasticity, negatively influencing the disease course. In the present study, we aimed to explore the influence of the proinflammatory cytokine IL-1&beta, on peculiar features of associative Hebbian synaptic plasticity, such as input specificity, using the paired associative stimulation (PAS). In 33 relapsing remitting-MS patients and 15 healthy controls, PAS was performed on the abductor pollicis brevis (APB) muscle. The effects over the motor hot spot of the APB and abductor digiti minimi (ADM) muscles were tested immediately after PAS and 15 and 30 min later. Intracortical excitability was tested with paired-pulse transcranial magnetic stimulation (TMS). The cerebrospinal fluid (CSF) levels of IL-1&beta, were calculated. In MS patients, PAS failed to induce long-term potentiation (LTP)-like effects in the APB muscle and elicited a paradoxical motor-evoked potential (MEP) increase in the ADM. IL-1&beta, levels were negatively correlated with the LTP-like response in the APB muscle. Moreover, IL-1&beta, levels were associated with synaptic hyperexcitability tested with paired-pulse TMS. Synaptic hyperexcitability caused by IL-1&beta, may critically contribute to alter Hebbian plasticity in MS, inducing a loss of topographic specificity.

Introduction: Patients admitted to intensive neurorehabilitation facilities following neurological damage who developed SARS-CoV-2 infection during hospitalization have not yet been reported. Such patients are elderly, with severe disabling neurological syndromes, more likely have significant underlying comorbidities and develop fatal complications during the disease. We reported clinical features, underlying comorbidities, laboratory and radiological findings, treatment and outcome of severely disabled neurological patients with SARS-CoV-2 infection. Methods: We retrospectively analyzed a group of 14 patients affected by severe neurological damage previously admitted to the Neurorehabilitation Unit of Neuromed Research Institute in Pozzilli, Italy, who developed confirmed COVID-19 during a SARS-CoV-2 outbreak occurred on March, 2020. Results: One out of 14 patients (7%) died after developing a severe acute respiratory distress. The remaining patients did not present any symptom or laboratory or radiological signs of the disease; neither new neurological deficit nor worsening of the pre-existing clinical manifestations were observed. Thirtheen patients had underlying comorbitidies (93%), the most frequent being hypertension (11 patients, 78.5%) and diabetes mellitus type II (7 patients, 50%). Long before infection, all patients were already under anticoagulant therapy with enoxaparin. Conclusions: In 13 out of 14 patients, the infection was asymptomatic; this is particularly intriguing considering their severe neurological clinical profile. According to the pivotal role played by inflammation and activation of blood coagulation in the pathogenesis of COVID-19, the anti-inflammatory and anticoagulant properties of enoxaparin, administered much earlier and during infection, could have favored an extremely benign disease course in these patients at high risk of poor outcome. Keywords: SARS CoV 2, neurological patients, neurological damage, Infection, Coronavirus

Studies of brain network connectivity improved understanding on brain changes and adaptation in response to different pathologies. Synaptic plasticity, the ability of neurons to modify their connections, is involved in brain network remodeling following different types of brain damage (e.g., vascular, neurodegenerative, inflammatory). Although synaptic plasticity mechanisms have been extensively elucidated, how neural plasticity can shape network organization is far from being completely understood. Similarities existing between synaptic plasticity and principles governing brain network organization could be helpful to define brain network properties and reorganization profiles after damage. In this review, we discuss how different forms of synaptic plasticity, including homeostatic and anti-homeostatic mechanisms, could be directly involved in generating specific brain network characteristics. We propose that long-term potentiation could represent the neurophysiological basis for the formation of highly connected nodes (hubs). Conversely, homeostatic plasticity may contribute to stabilize network activity preventing poor and excessive connectivity in the peripheral nodes. In addition, synaptic plasticity dysfunction may drive brain network disruption in neuropsychiatric conditions such as Alzheimer’s disease and schizophrenia. Optimal network architecture, characterized by efficient information processing and resilience, and reorganization after damage strictly depend on the balance between these forms of plasticity.

Background: Previous studies evidenced a link between metabolic dysregulation, inflammation, and neurodegeneration in multiple sclerosis (MS). Objectives: To explore whether increased adipocyte mass expressed as body mass index (BMI) and increased serum lipids influence cerebrospinal fluid (CSF) inflammation and disease severity. Methods: In this cross-sectional study, 140 consecutive relapsing-remitting (RR)-MS patients underwent clinical assessment, BMI evaluation, magnetic resonance imaging scan, and blood and CSF collection before any specific drug treatment. The CSF levels of the following cytokines, adipocytokines, and inflammatory factors were measured: interleukin (IL)-6, IL-13, granulocyte macrophage colony-stimulating factor, leptin, ghrelin, osteoprotegerin, osteopontin, plasminogen activator inhibitor-1, resistin, and Annexin A1. Serum levels of triglycerides, total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C) were assessed. Results: A positive correlation emerged between BMI and Expanded Disability Status Scale score. Obese RR-MS patients showed higher clinical disability, increased CSF levels of the proinflammatory molecules IL-6 and leptin, and reduced concentrations of the anti-inflammatory cytokine IL-13. Moreover, both the serum levels of triglycerides and TC/HDL-C ratio showed a positive correlation with IL-6 CSF concentrations. Conclusion: Obesity and altered lipid profile are associated with exacerbated central inflammation and higher clinical disability in RR-MS at the time of diagnosis. Increased adipocytokines and lipids can mediate the negative impact of high adiposity on RR-MS course.

Clinical deterioration of relapsing–remitting MS (RR-MS) patients reflects not only the number and severity of overt inflammatory and demyelinating episodes, but also subtle central damage caused by persistent exposure to inflammatory molecules. To explore the correlation between levels of CSF inflammatory molecules at the time of diagnosis and both demographic and clinical characteristics of a large sample of RR-MS patients, as well as the predictive value of cytokine levels on their prospective disease course. In 205 patients diagnosed with RR-MS, we measured at the time of diagnosis the CSF levels of inflammatory molecules. Clinical and MRI evaluation was collected at the time of CSF withdrawal and during a median follow-up of 3 years. The time interval between the first anamnestic episode of focal neurological dysfunction and RR-MS diagnosis was the main factor associated with high CSF levels of IL-6 and IL-8. Furthermore, elevated CSF levels of these cytokines correlated with enhanced risk of clinical and radiological disease reactivation, switch to second-line treatments, and with disability progression in the follow-up. Delayed diagnosis and treatment initiation are associated with higher CSF levels of IL-6 and IL-8 in RR-MS, leading to worsening disease course and poor response to treatments.

Background In the early phases of relapsing-remitting multiple sclerosis (RR-MS), a clear correlation between brain lesion load and clinical disability is often lacking, originating the so-called clinico-radiological paradox. Different factors may contribute to such discrepancy. In particular, synaptic plasticity may reduce the clinical expression of brain damage producing enduring enhancement of synaptic strength largely dependent on neurotrophin-induced protein synthesis. Cytokines released by the immune cells during acute inflammation can alter synaptic transmission and plasticity possibly influencing the clinical course of MS. In addition, immune cells may promote brain repair during the post-acute phases, by secreting different growth factors involved in neuronal and oligodendroglial cell survival. Platelet-derived growth factor (PDGF) is a neurotrophic factor that could be particularly involved in clinical recovery. Indeed, PDGF promotes long-term potentiation of synaptic activity in vitro and in MS and could therefore represent a key factor improving the clinical compensation of new brain lesions. The aim of the present study is to explore whether cerebrospinal fluid (CSF) PDGF concentrations at the time of diagnosis may influence the clinical course of RR-MS. Methods At the time of diagnosis, we measured in 100 consecutive early MS patients the CSF concentrations of PDGF, of the main pro- and anti-inflammatory cytokines, and of reliable markers of neuronal damage. Clinical and radiological parameters of disease activity were prospectively collected during follow-up. Results CSF PDGF levels were positively correlated with prolonged relapse-free survival. Radiological markers of disease activity, biochemical markers of neuronal damage, and clinical parameters of disease progression were instead not influenced by PDGF concentrations. Higher CSF PDGF levels were associated with an anti-inflammatory milieu within the central nervous system. Conclusions Our results suggest that PDGF could promote a more prolonged relapse-free period during the course of RR-MS, without influencing inflammation reactivation and inflammation-driven neuronal damage and likely enhancing adaptive plasticity.

Background: Synaptic plasticity, the basic mechanism of clinical recovery after brain lesion, can also remarkably influence the clinical course of multiple sclerosis (MS). Physical rehabilitation represents the main treatment option to promote synaptic long-term potentiation (LTP) and to enhance spontaneous recovery of neurological deficits. Objectives: To overview the role of pharmacological treatment and physical rehabilitation in modulating LTP and enhancing clinical recovery in MS. Results: Drug-induced LTP enhancement can be effectively used to promote functional recovery, alone or combined with rehabilitation. Also, as inflammatory cytokines alter synaptic transmission and plasticity in MS, pharmacological resolution of inflammation can positively influence clinical recovery. Finally, physical exercise could be an independent factor able to preserve or enhance LTP reserve both influencing signaling pathways involved in plasticity induction and maintenance, and decreasing inflammation. Future directions: Better knowledge of LTP determinants may be useful to design specific strategies to promote recovery after a relapse and to reduce the progressive neurological deterioration in MS patients.

Background Pisa syndrome (PS) or lateral axial dystonia is often seen in patients with Parkinson's disease (PD). It is characterized by a marked and reversible lateral flexion of the trunk (LFT) more than 10°. Objective To assess the effectiveness of a program of postural exercises and assess the effectiveness in term of pattern of muscular hyperactivity. Methods A total of 6 patients with PD and PS enrolled in the program of 10 sessions of postural exercise (90 min/session). EMG of thoraco-lumbar paraspinal muscles was performed to detect the pattern of muscular hyperactivity. Outcomes were examined using the Unified Parkinson's Disease Rating Scale part II and part III, degree of LFT and Visual Analogues Scale for back pain. Results EMG showed two patterns of muscular hyperactivity; ipsilateral to the bending side and contralateral to the bending side. The exercise improved the outcomes in both groups. Patients with muscular hyperactivity ipsilateral to the bending side gained more improvements. Conclusion Our results show that the exercise may be considered as a possible treatment for patients with PD and PS irrespective of the pattern of muscular activation. The effectiveness of exercise differed according to the pattern of muscular activation.

Central neuropathic pain (CNP) is common and disabling among patients with multiple sclerosis (MS). The pathological mechanisms underlying CNP in MS are not well understood. We explored whether NGF is implicated in the pathogenesis of CNP in MS. We measured NGF concentration in the CSF of 73 patients affected by MS, 15 with and 58 without CNP and 14 controls. We found increased levels of NGF in the CSF of patients with CNP compared to patients without and to controls. This finding supports the hypothesis that NGF plays a role in MS related CNP.

Repetitive transcranial magnetic stimulation (rTMS) over primary motor cortex (M1) elicits changes in motor evoked potential (MEP) size thought to reflect short- and long-term forms of synaptic plasticity, resembling short-term potentiation (STP) and long-term potentiation/depression (LTP/LTD) observed in animal experiments. We designed this study in healthy humans to investigate whether STP as elicited by 5-Hz rTMS interferes with LTP/LTD-like plasticity induced by intermittent and continuous theta-burst stimulation (iTBS and cTBS). The effects induced by 5-Hz rTMS and iTBS/cTBS were indexed as changes in MEP size. We separately evaluated changes induced by 5-Hz rTMS, iTBS and cTBS applied alone and those induced by iTBS and cTBS delivered after priming 5-Hz rTMS. Interactions between 5-Hz rTMS and iTBS/cTBS were investigated under several experimental conditions by delivering 5-Hz rTMS at suprathreshold and subthreshold intensity, allowing 1 and 5 min intervals to elapse between 5-Hz rTMS and TBS, and delivering one and ten 5-Hz rTMS trains. We also investigated whether 5-Hz rTMS induces changes in intracortical excitability tested with paired-pulse transcranial magnetic stimulation. When given alone, 5-Hz rTMS induced short-lasting and iTBS/cTBS induced long-lasting changes in MEP amplitudes. When M1 was primed with 10 suprathreshold 5-Hz rTMS trains at 1 min before iTBS or cTBS, the iTBS/cTBS-induced after-effects disappeared. The 5-Hz rTMS left intracortical excitability unchanged. We suggest that STP elicited by suprathreshold 5-Hz rTMS abolishes iTBS/cTBS-induced LTP/LTD-like plasticity through non-homeostatic metaplasticity mechanisms. Our study provides new information on interactions between short-term and long-term rTMS-induced plasticity in human M1.

In this study in patients with Parkinson's disease (PD), off and on dopaminergic therapy, with and without L-dopa-induced dyskinesias (LIDs), we tested intermittent theta-burst stimulation (iTBS), a technique currently used for non-invasively inducing long-term potentiation (LTP)-like plasticity in primary motor cortex (M1). The study group comprised 20 PD patients on and off dopaminergic therapy (11 patients without and 9 patients with LIDs), and 14 age-matched healthy subjects. Patients had mild-to-moderate PD, and no additional neuropsychiatric disorders. We clinically evaluated patients using the Unified Parkinson's Disease Rating Scale (UPDRS) and the Unified Dyskinesia Rating Scale (UDysRS). The left M1 was conditioned with iTBS at 80% active motor threshold intensity. Twenty motor evoked potentials (MEPs) were recorded from right first interosseous muscle before and at 5, 15 and 30 min after iTBS. Between-group analysis of variance (ANOVA) testing healthy subjects versus patients with and without LIDs, on and off therapy showed a significant interaction between factors "Group" and "Time". After iTBS, MEP amplitudes in healthy subjects increased significantly at 5, 15 and 30 min (p

Theta-burst stimulation (TBS) is currently used for inducing long-lasting changes in primary motor cortex (M1) excitability. More information is needed on how M1 is involved in early motor learning (practice-related improvement in motor performance, motor retention and motor consolidation). We investigated whether inhibitory continuous TBS (cTBS) is an effective experimental approach for modulating early motor learning of a simple finger movement in healthy humans. In a short task, 11 subjects practised 160 movements, and in a longer task also testing motor consolidation ten subjects practised 600 movements. During both experiments subjects randomly received real or sham cTBS over the left M1. Motor evoked potentials were tested at baseline and 7 min after cTBS. In the 160-movement experiment to test motor retention, 20 movements were repeated 30 min after motor practice ended. In the 600-movement experiment motor retention was assessed 15 and 30 min after motor practice ended, motor consolidation was tested by performing 20 movements 24 h after motor practice ended. Kinematic variables - movement amplitude, peak velocity and peak acceleration - were measured. cTBS significantly reduced the practice-related improvement in motor performance of finger movements in the experiment involving 160 movements and in the first part of the experiment involving 600 movements. After cTBS, peak velocity and peak acceleration of the 20 movements testing motor retention decreased whereas those testing motor consolidation remained unchanged. cTBS over M1 degrades practice-related improvement in motor performance and motor retention, but not motor consolidation of a voluntary finger movement.

We investigated abnormal premotor to motor (PMd-to-M1) connectivity in Parkinson's disease (PD) with repetitive transcranial magnetic stimulation (rTMS). We studied 28 patients off and on dopaminergic therapy and 28 healthy subjects. We delivered 5 Hz rTMS over M1 before and after conditioning PMd with 5 Hz rTMS. In healthy subjects, motor-evoked potentials (MEPs) elicited by M1-rTMS were facilitated and PMd-rTMS left MEPs unchanged. In patients, before PMd-rTMS, M1-rTMS induced no MEP facilitation, whereas after PMd-rTMS, it significantly facilitated MEPs only when patients were on therapy. In the second experiment, we delivered M1-rTMS under 3 different attention-demanding tasks: eyes closed, attention directed to the stimulated hand, and attention directed to the nonstimulated hand. In healthy subjects, a more pronounced MEP facilitation was present when subjects directed attention to the stimulated hand. In patients, the MEP facilitation was present when attention was directed to the stimulated hand only when patients were on therapy. Finally, we delivered M1-rTMS in patients on therapy while they were looking at the stimulated hand, before and after 1 Hz PMd-rTMS. PMd-rTMS reduced the attention-induced MEP facilitation. We conclude that in addition to abnormal M1 plasticity, the reduced MEP facilitation in PD also reflects altered PMd-to-M1 connectivity.

Theta-burst stimulation (TBS) is a technique that elicits long-lasting changes in the excitability of human primary motor cortex (M1). Tonic contraction of the target muscle modifies the aftereffects of TBS, whereas interactions between phasic muscle contraction and the aftereffects of TBS are unknown. In this paper, we investigated whether phasic voluntary movements influence TBS-induced changes in M1 excitability. We examined whether a brief sequence of phasic finger movements performed by healthy humans before both intermittent TBS (iTBS) and continuous TBS (cTBS) influences TBS-induced aftereffects. Ten healthy subjects underwent iTBS and cTBS. To evaluate the TBS-induced aftereffects on M1 excitability, single TMS pulses were given over the FDI motor area before (T0) and 5 (T1), 15 (T2), and 30 min (T3) after TBS. To find out whether finger movements influenced the TBS-induced aftereffects, we tested motor-evoked potentials (MEPs) size by single TMS pulses at T0, immediately after movements, and at T1–T3. We also measured the kinematic variables mean amplitude and mean peak velocity of the movements. When no phasic voluntary movements preceded TBS, iTBS elicited facilitatory and cTBS elicited inhibitory aftereffects on MEP size. Conversely, movements performed before TBS elicited significant changes in the direction of the TBS-induced aftereffects. iTBS produced inhibitory instead of facilitatory aftereffects and cTBS produced facilitatory instead of inhibitory aftereffects. Finger movements alone had no effects on MEPs size tested with single-pulse TMS. Peripheral electrical stimulation had no effect on iTBS-induced aftereffects. Repeated phasic finger movements interfere with TBS-induced aftereffects probably by modulating mechanisms of brain metaplasticity.

We investigated whether human attentional processes influence the size of the motor evoked potentials (MEP) facilitation and the duration of the cortical silent period (CSP) elicited by high-frequency repetitive transcranial magnetic stimulation (rTMS). In healthy subjects we assessed the effects of 5 Hz-rTMS, delivered in trains of 10 stimuli at suprathreshold intensity over the hand motor area, on the MEP size and CSP duration in different attention-demanding conditions: "relaxed," "target hand," and "non-target hand" condition. We also investigated the inhibitory effects of 1 Hz-rTMS conditioning to the premotor cortex on the 5 Hz-rTMS induced MEP facilitation. F-waves evoked by ulnar nerve stimulation were also recorded. rTMS trains elicited a larger MEP size facilitation when the subjects looked at the target hand whereas the increase in CSP duration during rTMS remained unchanged during the three attention-demanding conditions. The conditioning inhibitory stimulation delivered to the premotor cortex decreased the MEP facilitation during the "target hand" condition, leaving the MEP facilitation during the other conditions unchanged. None of the attentional conditions elicited changes in the F wave. In healthy subjects attentional processes influence the size of the MEP facilitation elicited by high-frequency rTMS and do so through premotor-to-motor connections.

We evaluated the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) on motor performance and motor learning of a rapid index finger movement. Two groups of healthy right-handed subjects underwent either "real" rTMS (1800 stimuli over the first dorsal interosseous (FDI) muscle hot spot given at 5 Hz and intensity of 90% of resting motor threshold-RMT) or "sham" stimulation. Both groups performed 60 rapid abductions of the right index finger before and after rTMS. The kinematic variables measured were amplitude, duration, peak velocity and peak acceleration. We also evaluated RMT and motor-evoked potential (MEP) amplitude before, 5 and 30 min after rTMS. In both groups practice significantly increased peak velocity, peak acceleration and amplitude and decreased movement duration independently from the type of intervention ("real" and "sham"). "Real" rTMS significantly increased cortical excitability as measured by MEP amplitude whereas "sham" rTMS did not. In our study, 5 Hz rTMS failed to improve either the motor performance or the motor learning of a rapid index-finger abduction despite the increase in cortical excitability of the primary motor cortex. Since motor behaviour engages a distributed cortical and subcortical neuronal network, excitatory conditioning of the primary motor cortex is probably not sufficient to influence the behavioural output.

Introduction Recent studies have suggested that the cerebellum may be involved in the pathophysiology of resting tremor in patients with Parkinson's disease (PD). The aim of the study was to investigate the effects of cerebellar continuous theta burst stimulation (cTBS) on cerebello-thalamo-cortical connectivity and resting tremor in PD patients. Methods Thirteen PD patients and ten healthy subjects underwent two experimental sessions: (i) ‘real’ cTBS, delivered over the cerebellar hemisphere and (ii) ‘sham’ cerebellar cTBS, delivered over the neck muscles. The two sessions were performed at least one week apart. The effects of ‘real’ and ‘sham’ cerebellar cTBS were quantified as excitability changes in the contralateral primary motor cortex or as possible changes in resting tremor in the ipsilateral hand. Primary motor cortex excitability was assessed by recording the input/output curve of the motor-evoked potentials from the contralateral first dorsal interosseous muscle. Results Resting tremor was rated clinically and objectively assessed by means of kinematic techniques. ‘Real’ cerebellar cTBS, though not ‘sham’ cerebellar cTBS, reduced the excitability in the contralateral primary motor cortex both in healthy subjects and in patients with PD. There was no significant change in rest tremor severity, as assessed by a clinical examination or kinematic techniques, after either ‘real’ or ‘sham’ cerebellar cTBS in patients. Lastly, there was no correlation between individual changes in M1 excitability and clinical or kinematic measures of resting tremor in patients. Conclusion The cerebello-thalamo-cortical connectivity, as tested by cTBS, is not predominantly involved in the generation of resting tremor in PD.

Introduction In migraine most studies report an interictal deficit of habituation of visual-evoked potentials (VEP-hab) and reduced thresholds for phosphene induction (PT) by transcranial magnetic stimulation (TMS). We searched for a possible correlation between VEP-hab and PT in migraine patients and healthy controls to test whether they reflect the same pathophysiological abnormality. Methods We assessed PT and VEP-hab measured as the percentage change of N1/P1 amplitude over six blocks of 100 responses in 15 healthy volunteers (HV) and in 13 episodic migraineurs without aura (MO) between attacks. Results were compared using Mann-Whitney U test. Interrelationships were examined using Spearman's correlation. Results In MO patients VEP-hab was reduced compared to HV ( p = 0.001), while PT were not significantly different between HV and MO. There was no correlation between PT and VEP-hab in either group of participants. Conclusions We confirm that in interictal migraine VEP habituation is deficient, but magnetophosphene threshold normal. VEP-hab and PT were not correlated with each other in healthy controls or in migraineurs. This finding suggests that they index different facets of cortical excitability in migraine, i.e. a punctual normal measure of the cortical activation threshold for PT and a dynamic response pattern to repeated stimuli for VEP habituation.

Introduction somatosensory temporal discrimination threshold (STDT) measures the ability to perceive two stimuli as being sequential. Altered STDT has been reported in Parkinson's disease (PD). The cerebellum seems to play a role in the pathophysiology of PD, and may consequently be involved in the pathophysiology of STDT abnormalities. Methods STDT was investigated in fifteen PD patients who underwent real and sham cerebellar continuous theta burst stimulation (cTBS) in the OFF condition. Eight patients underwent a further real cTBS session in ON condition. STDT was measured on both hands before, 5 and 25 min after real and sham cTBS delivered over the cerebellar hemisphere ipsilateral to the more affected side. We controlled the efficacy of our protocol by monitoring primary motor cortex (M1) excitability. Ten healthy subjects acted as control group. Results STDT values were increased in PD patients in the OFF condition compared with healthy subjects and PD patients in the ON condition. In PD patients OFF condition, real but not sham cerebellar cTBS, significantly reduced STDT values only in the hand ipsilateral to the stimulated cerebellar hemisphere. Cerebellar cTBS also decreased motor evoked potentials (MEP) size in the contralateral M1. When PD patients were tested in the ON condition, cerebellar cTBS failed to modify STDT values. Conclusion cerebellar cTBS improved STDT values in PD patients exclusively in OFF condition. We hypothesize that cerebellar stimulation partially compensates for increased STDT values only when patients are OFF dopaminergic therapy. This suggests that the cerebellum may act as compensatory system in PD.

Mirror movements (MMs) occur on the contralateral side of a limb being used intentionally. Because few families with congenital MMs and no other neurological signs have been reported, the underlying mechanisms of MMs are still not entirely clear. We report on the clinical, genetic, neurophysiological and neuroimaging findings of 10 of 26 living members of a novel four-generation family with congenital MMs. DCC and RAD51 were sequenced in affected members of the family. Five of the ten subjects with MMs underwent neurophysiological and neuroimaging evaluations. The neurophysiological evaluation consisted of electromyographic (EMG) mirror recordings, investigations of corticospinal excitability, and analysis of interhemispheric inhibition using transcranial magnetic stimulation techniques. The neuroimaging evaluation included functional MRI during finger movements. Eight (all females) of the ten members examined presented MMs of varying degrees at the clinical assessment. Transmission of MMs appears to have occurred according to an autosomal-dominant fashion with variable expression. No mutation in DCC or RAD51 was identified. EMG mirror activity was higher in MM subjects than in healthy controls. Short-latency interhemispheric inhibition was reduced in MM subjects. Ipsilateral motor-evoked potentials were detectable in the most severe case. The neuroimaging evaluation did not disclose any significant abnormalities in MM subjects. The variability of the clinical features of this family, and the lack of known genetic abnormalities, suggests that MMs are heterogeneous disorders. The pathophysiological mechanisms of MMs include abnormalities of transcallosal inhibition and corticospinal decussation.

Whereas numerous studies document the effects of dopamine medication and deep brain stimulation on motor function in patients with Parkinson’s disease, few have investigated deep brain stimulation-induced changes in sensory functions. In this study of 13 patients with Parkinson’s disease, we tested the effects of deep brain stimulation on the somatosensory temporal discrimination threshold. To investigate whether deep brain stimulation and dopaminergic medication induce similar changes in somatosensory discrimination, somatosensory temporal discrimination threshold values were acquired under four experimental conditions: (i) medication ON/deep brain stimulation on; (ii) medication ON/deep brain stimulation off; (iii) medication OFF/deep brain stimulation on; and (iv) medication OFF/deep brain stimulation off. Patients also underwent clinical and neuropsychological evaluations during each experimental session. Somatosensory temporal discrimination threshold values obtained in patients were compared with 13 age-matched healthy subjects. Somatosensory temporal discrimination threshold values were significantly higher in patients than in healthy subjects. In patients, somatosensory temporal discrimination threshold values were significantly lower when patients were studied in medication ON than in medication OFF conditions. Somatosensory temporal discrimination threshold values differed significantly between deep brain stimulation on and deep brain stimulation off conditions only when the patients were studied in the medication ON condition and were higher in the deep brain stimulation on/medication ON than in the deep brain stimulation off/medication ON condition. Dopamine but not subthalamic nucleus deep brain stimulation restores the altered somatosensory temporal discrimination in patients with Parkinson’s disease. Deep brain stimulation degrades somatosensory temporal discrimination by modifying central somatosensory processing whereas dopamine restores the interplay between cortical and subcortical structures.

In this paper we investigated the effects of intermittent theta-burst stimulation (iTBS) applied to the primary motor cortex on practice-related changes in motor performance. Seventeen healthy subjects underwent two experimental sessions, one testing real iTBS and the other testing sham iTBS. Before and after both iTBS sessions, the subjects practiced fast right index-finger abductions for a few minutes. As measures of cortical excitability we calculated resting motor threshold and motor-evoked potential amplitude. As measures of practice-related changes we evaluated the mean movement amplitude, peak velocity and peak acceleration values for each block. When subjects practiced the movement task, the three variables measuring practice-related changes improved to a similar extent during real and sham iTBS whereas cortical excitability increased only during real iTBS. In a further group of five healthy subjects we investigated the effect of real and sham iTBS on changes in motor performance after a longer task practice and found no significant changes in motor performance and retention after real and sham iTBS. From our results overall we conclude that in healthy subjects iTBS applied to the primary motor cortex leaves practice-related changes in an index finger abduction task unaffected. We suggest that iTBS delivered over the primary motor cortex is insufficient to alter motor performance because early motor learning probably engages a wide cortical and subcortical network.